Intermediates for preparing acridines

ABSTRACT

Diphenyl-2-carboxaldehyde derivatives, prepared by reacting a diphenylamine-2-carboxylic acid benzenesulfonyl-hydrazide with a base and hydrazine, semicarbazide, thiosemi-carbazide or phenylhydrazine, are reacted with a mineral acid to produce acridines. The acridines are useful as intermediates for preparing 9-aminoalkylacridans having pharmacodynamic activity.

United States Patent Anderson et al.

[ 1 Sept. 19, 1972 [54] INTERMEDIATES FOR PREPARING ACRIDINES [72] Inventors: Elvin L. Anderson, Moorestown,

N.J.; Harold Graboyes, Philadelphia, Pa.

[73] Assignee: Smith Kline & French Laboratories,

Philadelphia, Pa.

I22] Filed: Feb. 25, 1971 [21] Appl. No.: 118,976

Related US. Application Data [63] Continuation-impart of Ser. No. 732,869, May

29, 1968, Pat. No. 3,625,945.

[52] US. Cl. ..260/566 B, 2'6O/552 SC, 260/556 B [51] Int. Cl ..C07c 1 19100.

[58] Field of Search ..260/566 B, 556 B [56] References Cited UNITED STATES PATENTS 3,290,147 12/1966 Mattor et al..... ...260/566 B X OTHER PUBLICATIONS Brown et al., J. Chem. Soc. (London) (1958), 1843.

Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwartz Attorney-William 1-l. Edgerton, Richard D. Foggio, Joan S. Keps, Alan D. Lourie and Joseph A. Marlino [57] ABSTRACT preparing 9-aminoalkylacridans having pharmacodynamic activity.

4 Claims, No Drawings INTERMEDIATES FOR PREPARING ACRIDINES This application is a continuation-in-part of Ser. No. 732,869, filed May 29, 1968 now U.S. Patent No. 3,625,945.

This invention relates to new diphenyl-Z-carboxaldehyde derivatives which are useful as intermediates for preparing acridines.

The acridines prepared from the intermediates of this invention are represented by the following formula:

FORMULA I 35100bL C. for about -180 minutes to give a 9- aminoalkylacridan which is, or is an intermediate for, a pharrnacodynamically active compound as described in U.S. Pat. No. 3,131,190. These pharrnacodynamically active 9-aminoalkylacridans have central nervous system activity and are useful as tranquilizers, ataractics, antidepressants, antiemetics, antihistaminics, antispasmodics and anti-inflammatory agents.

An advantageous compound of Formula I is that in which R is chloro, in particular, in the 2-position, that compound being 2-chloroacridine. This acridine is an intermediate in the preparation of 9-aminoalkyl-2- chloro-acridans, in particular, 2-chloro-9- dimethylaminopropylacridan which is a known tranquilizing agent, Simpson et al., Current Therapeutic Research 8:447-451 (1966) and Claghom et al., Psychosomatics 82212-215 (1967).

The process for preparing the acridines of Formula I using the intermediates of this invention is represented schematically as follows:

FORMULA II FORMULA III R4 R *-t R R CH OONHNHSOr-Ar LII in which:

R is hydrogen, halogen having an atomic weight of less than 80, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethylsulfonyl, dimethylsulfamoyl or lower alkylthio;

R and R are hydrogen, halogen having an atomic weight of less than 80, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethylsulfonyl, dimethylsulfamoyl or lower alkylthio, at least one of R and R being hydrogen;

1 0 N l g R218 A 1 NH N112;

I s NHENH: or ILH-Q; and

Ar is phenyl, tolyl preferably p-tolyl or dihalophenyl preferably 2,5-dichlorophenyl. The intermediates of this invention are represented by Formula 111 above.

Preferred intermediates of this invention are represented by Formula 111 above when R, is

and one of R and R is chloro and the other is hydrogen, the chloro substituent being in the position para to the attachment of the nitrogen atom.

According to the above process, a diphenylamine-Z- carboxylic acid benzenesulfonylhydrazide of Formula 11 is reacted with a base such as an alkali metal hydroxide, for example, sodium or potassium hydroxide, or an alkali metal carbonate, for example sodium or potassium carbonate, and a member selected from the group consisting of hydrazine, semicarbazide, thiosemicarbazide and phenylhydrazine to give a diphenylamine-Z- carboxaldehyde derivative of Formula II]. This reaction is carried out in an organic solvent preferably a hydroxylic solvent such as, for example, fi-ethoxyethanol, B- methoxyethanol, ethylene glycol, butanol or amyl alcohol, advantageously in an aqueous solution with a water miscible hydroxylic solvent such as B-ethoxyethanol or B-methoxyethanol. The reaction is carried out at elevated temperature preferably about 200 C., conveniently at reflux temperature.

The above prepared diphenylamine-Z-carboxaldehyde derivatives are reacted with a mineral acid such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid to give the acridines. The reaction is carried out in an organic solvent, for example, a lower alkanoic acid such as acetic or formic acid or a hydroxylic solvent such as B-ethoxyethanol, B-methoxyethanol or ethylene glycol, preferably a lower alkanoic acid. Preferably, the reaction is carried out at elevated temperature, such as, for example, about 100-200 C. I

The diphenylamine-2-carboxylic acid benzenesulfonylhydrazide compounds are prepared as follows:

1. by reacting a diphenylamine-2-carboxylic' acid with a chlorinating agent, for example, thionyl chloride, to give the corresponding carboxylic acid chloride and reacting the acid chloride with a benzenesulfonylhydrazine or 2. by reacting a lower alkyl ester of a diphenylamine- 2-carboxylic acid with hydrazine and benzenesulfonyl chloride.

The diphenylamine-Z-carboxylic acids are either known to the art or are prepared by known methods, for example, by reacting an aniline with an ohalobenzoic acid or by reacting an o-aminobenzoic acid with a halobenzene.

The following examples are not limiting but are illustrative of this invention.

EXAMPLE 1 A mixture of 247.5 g. of 4-chlorodiphenylamine-2- carboxylic acid, 135 g. of thionyl chloride and two liters of cyclohexane is heated at reflux for one hour with mechanical stirring. The resulting solution is cooled to 4050 C. and 223 g. of p-toluene'sulfonylhydrazine is added. The mixture is then heated under reflux for six hours with stirring, then cooled and filtered. The solid material is dried in vacuo to give 4'- chlorodiphenylamine-2-carboxylic acid p-toluenesulfonyl-hydrazide.

A mixture of 104 g. of 4-chlorodiphenylamine-2- carboxylic acid p-toluenesulfonylhydrazide, 50 ml. of ION sodium hydroxide, 400 ml. of B-ethoxyethanol, 250 ml. of water and 15 g. of 85 percent hydrazine hydrate is heated at reflux for two hours with mechanical stirring. The mixture is cooled and filtered. The solid material is dried in vacuo to give 4-chlorodiphenylamine-Z-carboxaldehyde azine.

A mixture of 131 g. of 4'-chlorodiphenylamine-2- carboxaldehyde azine, 400 ml. of glacial acetic acid and 122 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for one hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and'filtered. Drying the solid material in vacuo gives 2-chloroacridine.

EXAMPLE 2 A mixture of 50 g. of 4'-trifluoromethyldiphenylamine-2-carboxylic acid, 24 g. of thionyl chloride and 500 ml. of cyclohexane is heated at reflux with mechanical stirring for one hour. The solution is cooled to 40-50 C. and 37.2 g. of p-toluenesulfonylhydrazine is added. The resulting mixture is heated for six hours at reflux, cooled and the insoluble solid is removed by filtration and dried in vacuo to give 4-trifluoromethyldiphenylamine-2-carboxylic acid p-toluene-sulfonylhydrazide.

A mixture of 272 g. of 4'-trifluoromethyldiphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide, 120 ml. of ION sodium hydroxide, 1.1 liter of B-ethoxyethanol, 680 ml. of water and 36.5 g. of 85 percent hydrazine hydrate is heated at reflux with mechanical stirring for two hours. The mixture is cooled and the solid removed by filtration and dried in vacuo to give 4'- trifluoromethyldiphenylamine-Z-carboxaldehyde azine.

A mixture of 90 g. of 4'-trifluoromethyldiphenylamine-2-carboxaldehyde azine, 270 ml. of glacial acetic acid and 73 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for one hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The solidmaterial is removed by filtration and dried in vacuo to give 2-trifluoromethylacridine.

EXAMPLE 3 A mixture of 156.5 g. of o-chlorobenzoic acid, 167.2 g. of p-(n-buty1)aniline, 69 g. of potassium carbonate, 1 g. of copper-bronze powder and 350 ml. of isoamyl alcohol is heated at reflux with mechanical stirring for four hours. During this time the water which formed is removed by azeotropic distillation. The inorganic salts are removed by filtration and 30 ml. of glacial acetic acid is added to the filtrate. After cooling, the solid material is removed by filtration and dried in vacuo to give 4'-(n-butyl)diphenylamine-2-carboxylic acid.

A mixture of 26.9 g. of 4'-( n-butyl)diphenylamine-2- carboxylic acid, 13.2 g. of thionyl chloride and 270 ml. of benzene is heated at reflux with mechanical stirring for one hour. The solution is cooled to 4045 C. and 20.5 g. of p-toluenesulfonylhydrazine is added. The resulting mixture is heated at reflux for six hours, cooled to 5l0 C. and the insoluble solid removed by filtration and dried in vacuo to give 4'-(n-butyl)diphenylamine-2-carboxylic acid p-toluene-sulfonylhydrazide.

A mixture of 25 g. of 4-(n-butyl)diphenylamine-2- carboxylic acid p-toluenesulfonylhydrazide, 1 1.5 ml. of ION sodium hydroxide, ml. of ,B-ethoxyethanol, 60 ml. of water and 3.5 g. of 85 percent hydrazine hydrate is heated at reflux with mechanical stirring for two hours. The mixture is cooled and the solid removed by filtration and dried in vacuo to give 4-(n-butyl)diphenylamine-2-carboxaldehyde azine.

A mixture of 7 g. of 4-(n-butyl)diphenylamine-2- carboxaldehyde azine, 25 ml. of glacial acetic acid and 10 ml. of concentrated hydrochloric acid isheated at reflux with mechanical stirring for 1 hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The solid material is removed by filtration, dissolved in ether and the residue is crystallized from hexane to give 2-(n-butyl)-acridine.

EXAMPLE 4 A mixture of 85 g. of 2'vchlorodiphenylamine-2-carboxylic acid, 47.4 g. of thionyl chloride and 850 ml. of benzene is heated at reflux with mechanical stirring for one hour. The solution is cooled to 40-50 C., 76.5 g. of p-toluenesulfonylhydrazine is added and the resulting mixture is heated at reflux with stirring for six hours. The mixture is cooled to 5l0 C. and the solid material is removed by filtration and dried in vacuo to give 2-chlorodiphenylamine-2-carboxylic acid ptoluenesulfonylhydrazide.

A mixture of 138 g. of 2'-chlorodiphenylamine-2- carboxylic acid p-toluenesulfonylhydrazide, 66.2 ml. of ION sodium hydroxide, '550 ml. of B-ethoxyethanol, 250 ml. of water and 19.5 g. of 85 percent hydrazine hydrate is heated at reflux with mechanical stirring for two hours. The mixture is cooled and the solid material is removed by filtration and dried in vacuo to give 2'- chlorodiphenylamine-Z-carboxaldehyde azine.

A mixture of 51.5 g. of 2'-chlorodiphenylamine-2- carboxaldehyde azine, ml. of glacial acetic-acid and 48 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for one hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The precipitate is removed by filtration and dried chloroacridine.

EXAMPLE 5 A mixture of 155 g. of 2-trifluoromethyldipheny1amine-2-carboxylic,acid, 76.5 g. of thionyl chloride and 1600 ml. of benzene is heated at reflux with mechanical stirring for one hour. The solution is cooled to 4050 C., 123 g. of p-toluenesulfonylhydrazine is added and the resulting mixture is heated under reflux with stirring for 6 hours. The suspension is cooled and the insoluble solid is removed by filtration and dried in vacuo to give 2-trifluoromethyldiphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide.

A mixture of 166 g. of 2'trifluoromethyldiphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide, 74 ml. of lON sodium hydroxide, 665 ml. of ,B-ethoxyethanol, 415 ml. of water and 22 g. of 85 percent hydrazine hydrate is heated at reflux with mechanical stirring for two hours. The mixture is cooled and the insoluble solid is removed by filtration and dried in vacuo to give 2'-trifluorornethyldiphenylamine-2-carboxaldehy'de azine.

A mixture of 37.5 g. of 2'-trifluoromethyldiphenylamine-Z-carboxaldehyde azine, 113 ml. of glacial acetic acid and 30 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for 1 hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The insoluble solid is removed by filtration and dried in vacuo to give- 4-trifluoromethylacridine.

EXAMPLE 6 A mixture of 416 g. of 4'-chlorodiphenylamine-2- carboxylic acid p-toluenesulfonylhydrazide (prepared as in Example 1), 120 g. of sodium hydroxide, 1600 ml. of B-ethoxyethanol, 1200 ml. of water and 114.5 g. of semicarbazide hydrochloride is heated at reflux with mechanical stirring for 1.5 hours. To the hot solution is added an additional 600 ml. of water and the mixture is cooled. The solid material is removed by filtration and dried in vacuo to give 4'-chloro-diphenylamine-2-carboxaldehyde semicarbazone.

A mixture of 72 g. of 4'-chlorodiphenylarnine-2-carboxaldehyde semicarbazone, 200 ml. of glacial acetic acid and 61 ml. of concentrated hydrochloric acid is heated at reflux with stirring for 1 hour. The reaction mixture is worked up as in Example 1 to give 2- chloroacridine.

EXAMPLE 7' in vacuo to give 4-' heated at reflux with stirring for 2 hours. An additional 60 ml. of water is added to the hot solution. The mixture is cooled and filtered to give 3-bromodiphenylamine-2-carboxaldehyde thiosemicarbazone.

The above prepared thiosemicarbazone is refluxed with glacial acetic acid and concentrated hydrochloric acid by the procedure of Example 6 to give 3- bromoacridine and l-bromoacridine.

EXAMPLE 8 A mixture of 140 g. of 4-chlorodiphenylamine-2- carboxylic acid p-toluenesulfonylhydrazide (prepared as in Example 1), 27 g. of sodium hydroxide, 36.4 g. of phenylhydrazine, 500 ml. of B-ethoxyethanol and 200 ml. of water is heated at reflux with mechanical stirring for 2 hours. The mixture is cooled and the solid materia1 is removed by filtration and dried in vacuo to give 4- chlorodiphenylamine-2-carboxaldehyde phenylhydrazone.

A mixture of g. of 4'-chlorodiphenylamine-Z-carboxaldehyde phenylhydrazone, 200 ml. of glacial acetic acid and 33 ml. of concentrated sulfuric acid is heated at reflux with stirring for 1 hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered to give 2- chloroacridine.

EXAMPLE 9 A mixture of 52 g. of 4'-methylthiodiphenylamine-2- carboxylic acid, 26.4 g. of thionyl chloride and 600 ml. of benzene is heated at reflux with stirring for one hour. The solution is cooled to 4050 C. and 41 g. of ptoluenesulfonyl-hydrazine is added. The. resulting mixture is heated at reflux with stirring for 5 hours, cooled and the solid material removed by filtration and dried in vacuo to give 4'-methylthiodi-phenylamine-2-carboxylic acid p-toluenesulfonylhydrazide.

A mixture of 75 g. of 4'-methylthiodiphenylamine-2- carboxylic acid p-toluenesulfonylhydrazide, 35 ml. of ION sodium hydroxide solution, 320 ml. of B-ethoxyethanol, 200 ml. of water and 10 g. of percent hydrazine hydrate isheated at reflux with stirring for 2 hours. The mixture is cooled and the solid material is removed by filtration and dried in vacuo to give 4'- methylthiodiphenylamine-2-carboxa1dehyde azine.

A mixture of 7 g. of 4-methylthiodipheny1amine-2- carboxaldehyde azine, 25 ml. of glacial acetic acid and 7.5 m1. of concentrated hydrochloric acid is heated at reflux with stirring for 1 hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The insoluble solid is removed by filtration and dried in vacuo to give 2-methylthioacridine.

EXAMPLE 10 A mixture of 35 g. of 4-methyldiphenylamine-2-carboxylic acid, 24 g. of thionyl chloride and 500 ml. of cyclohexane is heated at reflux with stirring for 2 hours. The solution is cooled and 48 g. of 2,5- dichlorobenzenesulfonylhydrazine is added. The resulting mixture is heated at reflux for six hours, then cooled and filtered to give 4-methyldiphenylamine-2-carboxylic acid 2,5-dichlorobenzenesulfonyl-hydrazide.

A mixture of 27 g. of the above prepared 2,5- dichlorobenzenesulfonylhydrazide, 6.4 g. of sodium and filtered to give 4'-methyldiphenylamine-Z-carboxaldehyde azine.

A mixture of 7 g. of the above prepared azine, 25 ml. of formic acid and ml. of phosphoric acid is heated at reflux for 2 hours. The solution is diluted with ice and water, basified with sodium hydroxide and filtered to give 2-methylacridine.

EXAMPLE 1 1 A mixture of 43 g. of 2"-inethoxydiphenylamine-2- carboxylic acid, 24 g. of thionyl chloride and 500 ml. of cyclohexane is heated. at reflux with stirring for one hour. The solution is cooled to 45C. and 34.4 g. of benzenesulfonylhydrazine is added. The mixture is heated'for 6 hours at reflux, then cooled and filtered to give 2-methoxydiphenyl-amine-2-carboxylic acid benzenesulfonylhydrazide.

A mixture of 13 g. of the above prepared benzenesulfonylhydrazide, 3.8 g. of potassium hydroxide, 3.6 g. of phenylhydrazine and 50 ml. of ethylene glycol is heated at 200 C. with stirring for two hours. The mixture is cooled and filtered to give 2-rnethoxydiphenylamine-2 -carboxa1dehyde phenylhydrazone.

A mixture of 7.9 g. of 2'-methoxydiphenylamine-2- carboxaldehyde phenylhydrazone, 10 ml. of concentrated sulfuric acid and 50 ml. of ethylene glycol is heated at 150 C. for one hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered to give 4-methoxyacridine.

EXAMPLE l2 A'mixture of 34.5 g. of 4-trifluoromethyl-sulfonyldiphenylamine-Z-carboxylic acid, 13.5 g. of thionyl chloride and 200 ml. of cyclohexane is heated at reflux with stirring for one hour. The solution is'co oled to 4050 C. and 22.3 g. of p-toluenesulfonylhydrazine is added. The mixture is heated at reflux with stirring for 6 hours, then cooled and filtered to give 4'- trifluoromethylsulfonyldiphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide.

A mixture of 12.8 g. of the above prepared ptoluenesulfonylhydrazide, 3.5 g. of potassium carbonate, 45 ml. of B-methoxyethanol, 25 ml. of water and 1.5 g. of 85 percent hydrazine hydrate is heated at reflux for 2 hours with stirring. The mixture is cooled and filtered to give 4-trifluoromethylsulfonyldiphenylamine-2-carboxaldehyde azine.

A mixture of 8.8 g. of the above prepared azine, 7.5 ml. of concentrated hydrochloric acid and 20 ml. of B- ethoxyethanol is heated at reflux for 1 hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered to give 2- trifluoromethylsulfonylacridi'ne.

EXAMPLE 13 A mixture of 47 g. of 4'-(N,N-dimethylsulfamoyl)- diphenylamine-Z-carboxylic acid benzenesulfonylhydrazide (prepared from 4'-(N,N-dimethylsulfamoyl)diphenylamine-2-carboxylic acid by the procedure of Example 7), 12.0 g. of sodium hydroxide, 160 ml. of B-ethoxyethanol, 120 ml. of water and 1 1.4

of semicarbazide hydrochloride is heated at reflux with stirring for two hours. Water (60 ml.) is added to the hot solution and the mixture is cooled and filtered to give 4'-( N,N-dimethylsulfamoyl)diphenylamine-Z-carboxaldehyde semicarbazone. v

A mixture of 36 g. of the above prepared semicarbazone, 150 ml. of glacial acetic acid and 48 ml. of concentrated hydrochloric acid is heated at reflux with stirring for 1 hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered to give 2-(N,N-dimethylsulfamoyl)acridine.

EXAMPLE 14 A mixture of 9.5 g. of diphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide, 5 ml. of lON sodium hydroxide, 1.5 g. of 85 percent hydrazine hydrate, 50 ml. of B-methoxyethanol and 20 ml. of water is heated at reflux with stirring for 2 hours. The mixture-is cooled and filtered to give diphenylamine-2-carboxaldehyde azine.

A mixture of 5.7 g. of diphenylamine-Zcarboxaldehyde azine, 7.5 ml. of concentrated hydrochloric acid and 100 ml. of B-methoxyethanol is heated at 100 C. for two hours. The solution is diluted with water and ice, basified with aqueous sodium hydroxide solution and filtered to give acridine.

EXAMPLE 15 A mixture of 118 g. of 2-bromo-5-chlorobenzoic acid, 93 g. of aniline, 69 g. of potassium carbonate, 6 g. of copper-bronze powder and 500 m1. of water is heated at reflux for five hours with mechanical stirring. The mixture is cooled slightly and clarified byfiltration. The filtrate is cooled and acidified with concentrated hydrochloric acid. The solid which precipitates is filtered off, washed with water, dried and recrystallized from toluene to give 5-chloro-N-phenylanthranilic acid.

A mixture of 24.9 g. of 5-chloro-N-phenylanthranilic acid, 12.0 g of thionyl chloride and 250 ml. of benzene is heated at reflux with mechanical stirring for one hour. The resulting solution is cooled to 4050 C. and 18.6 g. of p-toluenesulfonylhydrazine is added. The resulting mixture is heated at reflux with stirring for four hours and cooled. The solid material is filtered off, washed with benzene, dried and recrystallized from methanol to give 5-chloro-N-phenyl-anthranilic acid ptoluenesulfonylhydrazide.

A mixture of 17 g. of 5-chloro-N-phenylanthranilic acid p-toluenesulfonylhydrazide, 8 ml. of lON sodium hydroxide, 70 ml. of B-ethoxyethanol, 50 ml. of water and 3 g. of percent hydrazine hydrate is heated at reflux with mechanical stirring for 2 hours. The mixture is cooled and the solid material is filtered off, washed with water, dried and recrystallized from dimethylformamide to give 4-chlorodiphenylamine-2-carboxaldehyde azine.

A mixture of 4.6 g. of 4-chlorodiphenylamine-2-carboxaldehyde azine, 15 ml. of glacial acetic acid and 5 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for l hour. The resulting solution is quenched in a mixture of ice and water and basified with ammonia. The solid material is filtered off, washed with water and dried to give 2- chloroacridine.

EXAMPLE 16 A mixture of 75 g. of 2-bromo-4-trifluoromethylbenzoic acid, 55 g. of aniline, 41.5 g. of potassium carbonate, 4 g. of copper-bronze powder and 500 ml. of water is heated under reflux with mechanical stirring for 2 hours. The mixture is clarified by filtration and the filtrate is acidified to pH 1-2 with concentrated hydrochloric acid. The solid material is filtered ofi", washed with water, dried and recrystallized from toluene to give 4-trifluoromethyl-N-phenylanthranilic acid.

A mixture of 24 g. of 4-trifluoromethyl-N-phenylanthranilic acid, 10.4 g. of thionyl chloride and 300 ml. of benzene is heated at reflux with mechanical stirring for 1 hour. The resulting solution is cooled to 40-50 C. and 16.2 g. of p-toluenesulfonylhydrazine is added. The mixture is heated at reflux with mechanical stirring for four hours and then cooled. The solid material is filtered off, separated, washed with benzene, dried and recrystallized from B-ethoxyethanol to give 4-trifluoromethyl-N-phenylanthranilic acid p-toluenesulfonylhydrazide.

A mixture of 18 g. of 4-trifluoromethyl-N-phenylanthranilic acid p-toluenesulfonylhydrazide, 8 ml. of lON sodium hydroxide, 70 ml. of B-ethoxyethanol, 50 ml. of water and 3 g. of 85 percent hydrazine hydrate is heated at reflux for 2 hours with mechanical stirring. The mixture is cooled and the solid material is filtered off, washed with water, dried and recrystallized from [3- ethoxyethanol to give -trifluoromethyldiphenylamine- 2-carboxaldehyde azine.

A mixture of 5.3 g. of S-trifluoromethyldiphenylamine-Z-carboxaldehyde azine, 16 ml. of glacial acetic acid and 4 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for 1 hour. The resulting solution is quenched in ice and basified with ammonia. The solid material is filtered off, washed with water and dried to give 3-trifluoromethylacridine.

What is claimed is:

l. A compound of the formula:

R2 is I N CH 2. A compound according to claim 1 in which one of R and R4 is chloro and the other is hydrogen, the chloro substituent being in the position para to the attachment of the nitrogen atom.

3. A compound according to claim 1 in which R is 4. A compound according to claim 1 in which R is and R is chloro in the position para to the attachment of the nitrogen atom, said compound being 4'- chlorodiphenylamine-2-carboxaldehyde azine. 

2. A compound according to claim 1 in which one of R3 and R4 is chloro and the other is hydrogen, the chloro substituent being in the position para to the attachment of the nitrogen atom.
 3. A compound according to claim 1 in which R2 is
 4. A compound according to claim 1 in which R2 is 